Design of photoactivatable metallodrugs: Selective and rapid light-induced ligand dissociation from half-sandwich [Ru([9]aneS3)(N–N′)(py)]2+ complexes

• Published in: Inorganica Chimica Acta 2012-12, Vol.393, p.230-238
• Main Authors: Ragazzon, Giulio, Bratsos, Ioannis, Alessio, Enzo, Salassa, Luca, Habtemariam, Abraha, McQuitty, Ruth J., Clarkson, Guy J., Sadler, Peter J.
• Format: Article
• Language: English
• Subjects: Bioinorganic; Coordination complex; Macrocycle; Photochemistry; Pyridine ligand; Ruthenium
• ISSN: 0020-1693; 1873-3255
• DOI: 10.1016/j.ica.2012.06.031

Three new Ru(II) photoactivatable complexes with a face-capping tridentate macrocycle ligand are able to release a coordinated monodentate ligand selectively upon excitation with visible light and subsequently coordinate to DNA nucleobases. [Display omitted] ► Synthesis of new photoactive Ru(II) complexes with a face-capping tridentate macrocycle ligand. ► Light irradiation of complexes in aqueous solution and in the presence of model biomolecules. ► Oligonucleotide binding to [Ru([9]aneS3)(bpy)(py)][PF6]2 upon light irradiation. ► DFT excited-state calculations. The synthesis of the inert Ru(II) half-sandwich coordination compounds, [Ru([9]aneS3)(bpy)(py)][PF6]2 (1, [9]aneS3=1,4,7-trithiacyclononane, bpy=2,2′-bipyridine, py=pyridine), [Ru([9]aneS3)(en)(py)][PF6]2 (2, en=1,2-diaminoethane), and [Ru([9]aneN3)(en)(dmso-S)][PF6]2 (3, [9]aneN3=1,4,7-triazacyclononane), is reported along with the X-ray crystal structure of 1. We investigated whether these complexes have photochemical properties which might make them suitable for use as pro-drugs in photochemotherapy. Complexes 1 and 2 underwent rapid (minutes) aquation with dissociation of the pyridine ligand in aqueous solution when irradiated with blue light (λ=420 or 467nm). The photodecomposition of 3 was much slower. All complexes readily formed adducts with 9-ethylguanine (9-EtG) when this model nucleobase was present in the photolysis solution. Similarly, complex 1 formed adducts with the tripeptide glutathione (GSH), but only when photoactivated. HPLC and MS studies of 1 showed that irradiation promoted rapid formation of 1:1 (major) and 1:2 (minor) adducts of the oligonucleotide d(ATACATGCTACATA) with the fragment {Ru([9]aneS3)(bpy)}2+. Density functional theory (DFT) calculations and time-dependent DFT reproduced the major features of the absorption spectra and suggested that the lowest-lying triplet state with 3MLCT character, which is readily accessible via intersystem crossing, might be responsible for the observed dissociative behavior of the excited states. These complexes are promising for further study as potential photochemotherapeutic agents.